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Testosterone enters the cell, attaches to DNA, turns on protein production

Testosterone Replacement Reduces Mortality by Jeffrey Dach MD

A study published in the Journal of Clinical Endocrinology & Metabolism by Molly Shores examined 1,031 men over 4 years. All 1,031 had low testosterone (below 250), and a subgroup of 398 of the men were treated with testosterone supplementation. At the end of the observation period the treated men had 10.3% mortality compared to 20.7% for the untreated men.(1) Testosterone supplementation reduced mortality in half. This is a rather impressive result.

For Post-menopausal Diabetic Women, Testosterone is Found to be Beneficial

A study published in 2011 Diabetes Care by Elisabeth Wehr from Graz, Austria looked at testosterone levels in 875 postmenopausal women referred for coronary angiography who were followed for 7 years. The Diabetic women with the highest quartile testosterone levels had a 60 percent reduction in all-cause and cardiovascular mortality compared to the lowest quartile.(2)

A similar study in older men referred for coronary angiography published by Dr Lerchblaumin in 2012 Clinical Endocrinology found that a combination of low free testosterone and low vitamin D predicts mortality.(3)

Endocrine Society Now Recommended Testosterone Testing and Replacement for All Diabetic Males (4,5)

About a quarter of diabetic men will have subnormal testosterone levels putting them at (200-300%) increased risk of cardiovascular mortality. The Endocrine Society now recommends that diabetic men have testosterone levels checked and given Testosterone replacement when found low. (4,5) Testosterone replacement is no longer controversial in the mainstream literature.(6,7,8)

Above Image: Testosterone (T) enters the cell and, if 5-alpha-reductase is present, is converted into dihydrotestone (DHT). Upon steroid binding, the androgen receptor (AR) undergoes a conformational change and releases heat shock proteins (hsps). Phosphorylation (P) occurs before and / or after steroid binding. The AR translocates to the nucleus where dimerization, DNA binding, and the recruitment of coactivators occur. Target genes are transcribed (mRNA) and translated into proteins. Original work, adapted from the following sources: This figure is based on an original drawing by Dr. Marianne D Sadar (Meehan KL, Sadar MD. Androgens and androgen receptor in prostate and ovarian malignancies. Front Biosci. 2003 May 1;8:d780-800).” Courtesy of Wikimedia Commons

Context: Low testosterone levels in men have been associated with increased mortality. However, the influence of testosterone treatment on mortality in men with low testosterone levels is not known.
Objective: The objective of the study was to examine the association between testosterone treatment and mortality in men with low testosterone levels.
Design: This was an observational study of mortality in testosterone-treated compared with untreated men, assessed with time-varying, adjusted Cox proportional hazards regression models. Effect modification by age, diabetes, and coronary heart disease was tested a priori.
Setting: The study was conducted with a clinical database that included seven Northwest Veterans Affairs medical centers.
Patients: Patients included a cohort of 1031 male veterans, aged older than 40 yr, with low total testosterone [≤250 ng/dl (8.7 nmol/liter)] and no history of prostate cancer, assessed between January 2001 and December 2002 and followed up through the end of 2005.Main Outcome Measure: Total mortality in testosterone-treated compared with untreated men was measured.Results: Testosterone treatment was initiated in 398 men (39%) during routine clinical care. The mortality in testosterone-treated men was 10.3% compared with 20.7% in untreated men(P<0.0001) with a mortality rate of 3.4 deaths per 100 person-years for testosterone-treated men and 5.7 deaths per 100 person-years in men not treated with testosterone. After multivariable adjustment including age, body mass index, testosterone level, medical morbidity, diabetes, and coronary heart disease, testosterone treatment was associated with decreased risk of death (hazard ratio 0.61; 95% confidence interval 0.42–0.88; P = 0.008). Conclusions: In an observational cohort of men with low testosterone levels, testosterone treatment was associated with decreased mortality compared with no testosterone treatment.

OBJECTIVE We aimed to evaluate whether total testosterone (TT), free testosterone (FT), and sex hormone–binding globulin (SHBG) are associated with all-cause and cardiovascular mortality in a cohort of postmenopausal women.

RESEARCH DESIGN AND METHODS We measured TT and SHBG levels in 875 postmenopausal women who were referred for coronary angiography (during 1997–2000). FT was calculated according to the Vermeulen method. The main outcome measures were Cox proportional hazard ratios (HRs) for mortality from all causes and from cardiovascular causes.

RESULTS After a median follow-up time of 7.7 years, 179 women (20.5%) had died. There were 101 deaths due to cardiovascular disease (56.4% of all deaths). We found no association of FT, TT, and SHBG levels with mortality in all postmenopausal women.

In postmenopausal diabetic women, multivariable-adjusted HRs (with 95% CIs) in the fourth compared with the first FT quartile for all-cause and cardiovascular mortality were 0.38 (0.08–0.90), P = 0.025, and 0.28 (0.08–0.90), P = 0.032, respectively. We found no association of TT and SHBG with mortality in diabetic postmenopausal women.

Low levels of 25-hydroxyvitamin D (25(OH)D) and free testosterone (FT) are both associated with increased mortality.Experimental studies show a complex interplay of vitamin D and androgen metabolism suggesting that a deficiency of both hormones may be associated with a particularly adverse clinical outcome. OBJECTIVE: To evaluate the impact of parallel FT and 25(OH)D deficiency in a large cohort of older men. DESIGN:We measured total testosterone (TT), SHBG, and 25(OH)Dlevels in 2069 men who were routinely referred for coronary angiography (1997-2000).
MAIN OUTCOME MEASURES:Cox proportional hazard ratios (HRs) (with 95% confidence intervals) for mortality from all causes, cardiovascular, and non-cardiovascular causes according to combined deficiency of FT and 25(OH)D.
RESULTS:In multivariate adjusted analyses, we found an increased risk for all-cause mortality, cardiovascular and non-cardiovascular mortality for men in the lowest FT (HR 1.26 [1.03-1.54], 1.24 [0.96-1.60], and 1.39 [1.00-1.93], respectively) and 25(OH)D quartile (HR 1.77 [1.47-2.13], 1.65 [1.29-2.10], and 1.89 [1.38-2.60] respectively) compared to men in higher FT and 25(OH)D quartiles. There was no independent association of TT levels with mortality. Multivariate adjusted HRs progressively increased with the number of hormones (FT and 25(OH)D) in the lowest quartile (0 vs 2 hormone deficiencies:
2.11 [1.60-2.79] for all cause,
1.77 [1.23-2.55] for cardiovascular, and
2.33 [1.45-3.47] for non-cardiovascular mortality respectively).

CONCLUSION:A combined deficiency of FT and 25(OH)D is significantly associated with fatal events in a large cohort of men referred for coronary angiography.

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Endocrine society – measure testo in AODM Men

4) www.ncbi.nlm.nih.gov/pubmed/21896895 J Clin Endocrinol Metab. 2011 Sep;96(9):2643-51.
Update: Hypogonadotropic hypogonadism in type 2 diabetes and obesity.
Dandona P, Dhindsa S.Division of Endocrinology, State University of New York at Buffalo and Kaleida Health, Buffalo, New York 14209, USA.

Studies over the last few years have clearly established that at least 25% of men with type 2 diabetes have subnormal free testosterone concentrations in association with inappropriately low LH and FSH concentrations. Another 4% have subnormal testosterone concentrations with elevated LH and FSH concentrations.

The Endocrine Society, therefore, now recommends the measurement of testosterone in patients with type 2 diabetes on a routine basis. The subnormal testosterone concentrations are not related to glycosylated hemoglobin or duration of diabetes, but are associated with obesity, very high C-reactive protein concentrations, and mild anemia.

In addition, subnormal testosterone concentrations in these men are associated with a two to three times elevated risk of cardiovascular events and death in two early studies. Short-term studies of testosterone therapy in hypogonadal men with type 2 diabetes have demonstrated an increase in insulin sensitivity and a decrease in waist circumference. However, the data on the effect of testosterone replacement on glycemic control and cardiovascular risk factors such as cholesterol and C-reactive protein concentrations are inconsistent. As far as sexual function is concerned, testosterone treatment increases libido but does not improve erectile dysfunction and thus, phosphodiesterase inhibitors may be required. Trials of a longer duration are clearly required to definitively establish the benefits and risks of testosterone replacement in patients with type 2 diabetes and low testosterone.

Lower levels of anabolic hormones in older age are well documented. Several studies suggested that low insulin-like growth factor I (IGF-I) or testosterone levels were related to increased mortality. The aim of the present study was to investigate the combined influence of low IGF-I and low testosterone on all-cause mortality in men.
METHODS AND RESULTS:From two German prospective cohort studies, the DETECT study and SHIP, 3942 men were available for analyses. During 21,838 person-years of follow-up, 8.4% (n=330) of men died. Cox model analyses with age as timescale and adjusted for potential confounders revealed that men with levels below the 10th percentile of at least one hormone [hazard ratio (HR) 1.38 (95% confidence-interval (CI) 1.06-1.78), p=0.02] and two hormones [HR 2.88 (95% CI 1.32-6.29), p<0.01] showed a higher risk of all-cause mortality compared to men with non-low hormones. The associations became non-significant by using the 20th percentile as cut-off showing that the specificity increased with lower cut-offs for decreased hormone levels. The inclusion of both IGF-I and total testosterone in a mortality prediction model with common risk factors resulted in a significant integrated discrimination improvement of 0.5% (95% CI 0.3-0.7%, p=0.03).
CONCLUSIONS:Our results prove that multiple anabolic deficiencies have a higher impact on mortality than a single anabolic deficiency and suggest that assessment of more than one anabolic hormone as a biomarker improve the prediction of all-cause mortality.

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